2016
DOI: 10.1021/acs.jmedchem.5b01909
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Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance

Abstract: Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesiz… Show more

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Cited by 28 publications
(49 citation statements)
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“…Apraglutide is a novel GLP-2 analogue with very low clearance. Its few amino acid substitutions (Table 1; Wiśniewski et al, 2011;Wiśniewski et al, 2016) confer unique PK properties, namely very low clearance and high protein binding, that enable a long in vivo halflife without conjugation or other major modifications to the peptide. The direct comparisons reported here for apraglutide versus native hGLP-2 and other GLP-2 analogues currently in the clinic (teduglutide) or in clinical trials (glepaglutide) for the treatment of SBS show that apraglutide has superior PK and pharmacodynamic profiles.…”
Section: Discussionmentioning
confidence: 99%
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“…Apraglutide is a novel GLP-2 analogue with very low clearance. Its few amino acid substitutions (Table 1; Wiśniewski et al, 2011;Wiśniewski et al, 2016) confer unique PK properties, namely very low clearance and high protein binding, that enable a long in vivo halflife without conjugation or other major modifications to the peptide. The direct comparisons reported here for apraglutide versus native hGLP-2 and other GLP-2 analogues currently in the clinic (teduglutide) or in clinical trials (glepaglutide) for the treatment of SBS show that apraglutide has superior PK and pharmacodynamic profiles.…”
Section: Discussionmentioning
confidence: 99%
“…Peptide Synthesis. Peptides used in these studies were prepared as trifluoroacetic acid (TFA) salts by solid-phase peptide synthesis and purified by reverse-phase high performance liquid chromatography (HPLC) as previously described (Wiśniewski, et al 2011;Wiśniewski, et al 2016,). The peptide identities were verified by mass spectrometry.…”
Section: Methodsmentioning
confidence: 99%
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“…In the present pre-clinical study, we have examined the trophic effects of a novel long-acting human GLP-2R agonist, apraglutide (Wisniewski, 2016), on small intestinal and colonic weight and length, as well as small intestinal crypt-villus height and crypt number in mice, directly comparing the temporal responses to chronic treatment for 3, 7 and 10 weeks. Apraglutide is a new GLP-2 analogue which distinguish from other GLP-2 analogs such as teduglutide (Revestive ® /Gattex ® , Shire Inc.) due to its very low clearance, long elimination half-life (30 hours) and high plasma protein binding ((Hargrove, 2020) and data not shown).…”
Section: Introductionmentioning
confidence: 99%
“…A fair number of peptides of increased potency through modification with D-residues have also been reported 7,[9][10][11][12][13][14] . More recently, a systematic D-amino acid scan was used to identify GLP-2 (glucagon-like peptide-2) analogs with enhanced pharmacokinetics 15 . Consequently, a D-amino acid scan 16,17 conducted alongside the more common alanine scan 18,19 can serve to more fully interrogate the relationship between structure and function in novel peptides and proteins 20,21 .…”
mentioning
confidence: 99%